The central hypothesis of this program project is that altered mitochondrial function is a key determinant of metabolic syndrome. However while metabolic syndrome has been extensively characterized in muscle, liver, kidney and pancreas, little is known about how it impacts brain function. The potential importance of understanding the impact of metabolic syndrome on brain function is highlighted by two converging lines of evidence. Firstly, recent studies have strongly implicated impaired brain mitochondrial function in a host of neurodegenerative diseases, including Alzheimer's and temporal lobe epilepsy. Secondly, epidemiological studies have found a several fold enhancement in the total incidence of neurodegenerative diseases in patients with type 2 Diabetes Metlitus. Reduced brain mitochondria in people with severe insulin resistance may be a factor in this increased susceptibility. In project 3 we will take advantage of our recent developments of MRS methods for non-invasively imaging brain mitochondrial metabolic function to assess whether it is altered in three groups of subjects with metabolic syndrome. These groups are 1) insulin resistant offspring of parents with Type II diabetes, 2) elderly subjects and 3) patients with an identified mutation in a gene coding for mitochondrial tRNA. Recent MRS studies by the Shulman laboratory have shown that all three groups have altered muscle mitochondrial metabolism. Our general hypothesis in this project is that there are similar alterations in brain mitochondrial metabolism in the brain of these subjects as in the muscle and liver. This project will )rovide the first comprehensive study of metabolic syndrome to brain, and may provide new insight nto why subjects with metabolic syndrome are at increased risk of neurodegenerative disease.